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J. Biol. Chem., Vol. 278, Issue 43, 42214-42224, October 24, 2003

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RGD-containing Peptides Activate S6K1 through ₃ Integrin in Adult Cardiac Muscle Cells^*

Sundaravadivel Balasubramanian and Dhandapani Kuppuswamy¶

From the Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina and the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29425-2221

The enzyme p70S6 kinase (S6K1) is critical for cell growth, and we have reported its activation during cardiac hypertrophy. Because cardiac hypertrophy also involves integrin activation, we analyzed whether integrins could contribute to S6K1 activation. Using adult feline cardiomyocytes, here we report that integrin-interacting Arg-Gly-Asp (RGD) peptides activate S6K1 as observed by band shifting, kinase activity and phosphorylation at Thr-389 and Thr-421/Ser-424 of S6K1, and S6 protein phosphorylation. Perturbation of specific integrin function with blocking antibodies and by overexpressing the _1A cytoplasmic tail revealed that ₃ but not ₁ integrin mediates the RGD-induced S6K1 activation. This activation is focal adhesion complex-independent and is accompanied by the activation of extracellular signal-regulated kinases 1/2 (ERK) and mammalian target of rapamycin (mTOR). Studies using specific inhibitors and dominant negative c-Raf expression in cardiomyocytes indicate that the S6K1 activation involves mTOR, MEK/ERK, and phosphatidylinositol 3-kinase pathways and is independent of protein kinase C and c-Raf. Finally, addition of fluorescent-labeled RGD peptide to cardiomyocytes exhibits its internalization and localization to the endocytic vesicles, and pretreatment of cardiomyocytes with endocytic inhibitors reduced the S6K1 activation. These data suggest that RGD interaction with ₃ integrin and its subsequent endocytosis trigger specific signaling pathway(s) for S6K1 activation in cardiomyocytes and that this process may contribute to hypertrophic growth and remodeling of myocardium.

Received for publication, April 2, 2003 , and in revised form, August 4, 2003.

^* This work was supported by Program Project Grant HL-48788 from the National Institutes of Health, by Merit and REAP awards from the Research Service of the Department of Veterans Affairs, and by American Heart Association Postdoctoral Fellowship 0120540U (to S. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Gazes Cardiac Research Inst., 114 Doughty St., Charleston, SC 29425-2221. Tel.: 843-876-5067; Fax: 843-876-5068; E-mail: kuppusd{at}musc.edu.

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